7VUN

Design, modification, evaluation and cocrystal studies of novel phthalimides regulating PD-1/PD-L1 interaction

Summary for 7VUN

• Entry DOI: 10.2210/pdb7vun/pdb
• Descriptor: Programmed cell death 1 ligand 1, (2~{S},3~{S})-2-[[6-[(3-cyanophenyl)methoxy]-2-(2-methyl-3-phenyl-phenyl)-1,3-bis(oxidanylidene)isoindol-5-yl]methylamino]-3-oxidanyl-butanoic acid (3 entities in total)
• Functional Keywords: dimer, beta-sheet, structural protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 8
• Total formula weight: 117522.16

Authors

Cheng, Y.,Sun, C.L.,Chen, M.R.,Yang, P.,Xiao, Y.B. (deposition date: 2021-11-03, release date: 2022-09-14, Last modification date: 2024-11-13)

Primary citation

Sun, C.,Cheng, Y.,Liu, X.,Wang, G.,Min, W.,Wang, X.,Yuan, K.,Hou, Y.,Li, J.,Zhang, H.,Dong, H.,Wang, L.,Lou, C.,Sun, Y.,Yu, X.,Deng, H.,Xiao, Y.,Yang, P.
Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents.
Acta Pharm Sin B, 12:4446-4457, 2022

PubMed Abstract: Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind that of antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein, which was not reported before. A series of novel phthalimide derivatives from structure-based rational design was synthesized. was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC = 8.9 nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, exhibited a favorable safety profile with a LD > 5000 mg/kg and showed significant antitumor activity through promoting CD8 T cell activation. All these data suggest that acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.

PubMed: 36561991
DOI: 10.1016/j.apsb.2022.04.007

Experimental method

X-RAY DIFFRACTION (2.701 Å)